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Beer AACR article_May10_2011.full

  1. 1. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.RANDOMIZED TRIAL OF AUTOLOGOUS CELLULARIMMUNOTHERAPY WITH SIPULEUCEL-T IN ANDROGENDEPENDENT PROSTATE CANCERTomasz M Beer, Guy T Bernstein, John M Corman, et al.Clin Cancer Res Published OnlineFirst May 10, 2011. Updated Version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-10-3223 Author Author manuscripts have been peer reviewed and accepted for publication but have not yet Manuscript been edited. E-mail alerts Sign up to receive free email-alerts related to this article or journal. Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at pubs@aacr.org. Permissions To request permission to re-use all or part of this article, contact the AACR Publications Department at permissions@aacr.org. Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  2. 2. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RANDOMIZED TRIAL OF AUTOLOGOUS CELLULAR IMMUNOTHERAPY WITH SIPULEUCEL-T IN ANDROGEN DEPENDENT PROSTATE CANCERAuthors: Tomasz M. Beer1, Guy T. Bernstein2, John M. Corman3, L. Michael Glode4,Simon J. Hall5, Wayne L. Poll6, Paul F. Schellhammer7, Lori A. Jones8, Yi Xu8, Jelle W.Kylstra9, and Mark W. Frohlich8 for the PROTECT InvestigatorsAuthor affiliations: 1Oregon Health & Science University Knight Cancer Institute,Portland, OR; 2Center for Urologic Care, Bryn Mawr, PA; 3Virginia Mason MedicalCenter, Seattle, WA; 4University of Colorado Health Science Center, Aurora, CO;5 Mount Sinai School of Medicine, New York, NY; 6AKSM Clinical Research Corporation,Columbus, OH; 7Urology of Virginia, PC/Eastern Virginia Medical School, Norfolk, VA;8 Dendreon Corporation, Seattle, WA; 9Spectrum Pharmaceuticals, Irvine, CA.Corresponding author: Tomasz M. Beer, MD, Oregon Health & Science UniversityKnight Cancer Institute, 3303 SW Bond Ave, CH14R, Portland, OR 97239-3098, Email:beert@ohsu.edu, Phone: (503) 494-0365, Facsimile: (503) 494-6197.Running Title: Sipuleucel-T in Androgen Dependent Prostate CancerWord count: 3429Tables: 2Figures: 4Keywords: immunotherapy, autologous cellular immunotherapy, prostate cancer Page 1 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  3. 3. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Disclaimer: Results from this study have been presented in part at the 2007 AmericanAssociation for Cancer Research and American Society of Clinical Oncology annualmeetings.Statement of Translational Relevance: Sipuleucel-T is an autologous cellularimmunotherapy FDA-approved for the treatment of asymptomatic or minimallysymptomatic, metastatic castrate resistant prostate cancer, where it has beendemonstrated to significantly prolong overall survival. This randomized studyinvestigated sipuleucel-T earlier in the natural history of prostate cancer, in men withandrogen-dependent disease. It provides the first evidence that sipuleucel-T can affecta clinically relevant endpoint, PSA doubling time, proximal to overall survival. Increasedantigen presenting cell activation in the second, third, and boost doses of sipuleucel-Trelative to the first dose provides evidence of priming with the first dose, and boostingby subsequent infusions, indicative of the establishment of immunologic memory. Thisstudy also demonstrates that sipuleucel-T can generate a robust and sustained T cellresponse to the immunizing antigen in this patient population, and that this immuneresponse is maintained following a single booster infusion, which may be augmented insome patients. Page 2 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  4. 4. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.ABSTRACTPURPOSE: Sipuleucel-T, an autologous cellular immunotherapy, was investigated in arandomized, double-blind, controlled trial to determine its biologic activity in androgendependent prostate cancer (ADPC).EXPERIMENTAL DESIGN: Patients with prostate cancer detectable by serum prostatespecific antigen (PSA) following radical prostatectomy received 3 to 4 months ofandrogen suppression therapy, and were then randomized (2:1) to receive sipuleucel-T(n=117) or control (n=59). The primary endpoint was time to biochemical failure (BF)defined as serum PSA ≥ 3.0 ng/mL. PSA doubling time (PSADT), time to distant failure,immune response, and safety were also evaluated.RESULTS: Median time to BF was 18.0 months for sipuleucel-T and 15.4 months forcontrol (HR=0.936, P=0.737). Sipuleucel-T patients had a 48% increase in PSADTfollowing testosterone recovery (155 vs. 105 days, P=0.038). With only 16% of patientshaving developed distant failure, the treatment effect favored sipuleucel-T (HR=0.728,P=0.421). The most frequent adverse events in sipuleucel-T patients were fatigue,chills, and pyrexia. Immune responses to the immunizing antigen were greater insipuleucel-T patients at Weeks 4 and 13 (P<0.001, all) and were sustained prior toboosting as measured in a subset of patients a median of 22.6 months (range 14.3-67.3months) following randomization.CONCLUSIONS: No significant difference in time to BF could be demonstrated. Thefinding of increased PSADT in the sipuleucel-T arm is consistent with its biologic activityin ADPC. Long-term follow-up will be necessary to determine if clinically important Page 3 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  5. 5. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.events, such as distant failure, are affected by therapy. Treatment was generally welltolerated. Page 4 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  6. 6. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.INTRODUCTION Nineteen to 32 percent of men who undergo surgery for clinically localizedprostate cancer experience disease recurrence.1-4 An elevated prostate specific antigen(PSA) level is often the first and only sign of disease recurrence. Management ofpatients with a rising PSA remains uncertain. While those suspected of harboringlocally-persistent disease may benefit from radiation therapy, the majority of thesepatients have systemic disease. Systemic therapy with androgen suppression therapymay benefit some of these patients,5 but the optimal timing of its initiation remainsunclear6,7 and potential benefits must be weighed against considerable toxicities.7,8 Newtreatments with fewer side effects are needed. Sipuleucel-T is an autologous cellular immunotherapy composed of a patient’speripheral blood mononuclear cells (PBMC), including antigen presenting cells (APCs),that have been activated ex vivo with a recombinant fusion protein known as PA2024.PA2024 consists of a prostate antigen, prostatic acid phosphatase (PAP), fused togranulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator.Two randomized, double blind, controlled Phase 3 trials in metastatic castrate resistantprostate cancer provided initial evidence that sipuleucel-T prolongs survival,9,10 whichwas confirmed in a third Phase 3 trial with 512 men.11 To study the activity of sipuleucel-T in patients with androgen dependent prostatecancer (ADPC), a double-blind, controlled, randomized trial, PROTECT (PROvengeTreatment and Early Cancer Treatment, NCT00779402), was designed to examine timeto biochemical failure (BF, the primary endpoint defined as serum PSA ≥ 3.0 ng/mL),PSA doubling time (PSADT), time to distant failure, and overall survival. Page 5 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  7. 7. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.MATERIALS AND METHODSPatients Eligible patients had a rise in serum PSA as the only sign of disease recurrencefollowing a radical prostatectomy performed at least 3 months and not more than 10years prior to registration for histologically confirmed prostate cancer. Patients whoexperienced their first PSA recurrence within 2 years of initial therapy were eligibleregardless of the Gleason score; those who experienced their first PSA relapsebetween 2 and 10 years following initial therapy were eligible only if the Gleason scorewas ≥ 7. Other eligibility requirements included an Eastern Cooperative OncologyGroup (ECOG) performance status of 0 or 1, life expectancy of at least one year, andage between 18 and 80 years. Negative serology for human immunodeficiency virus,human T-lymphotropic virus type 1 or 2, and hepatitis B and C were required, as wereadequate hematologic, renal, and hepatic function. The tumor specimen had to bepositive for PAP by immunohistochemistry. Therapeutic PSA response to primarytherapy was required to have been < 0.4 ng/mL. If androgen ablation was given for aprevious PSA relapse, current PSA must have reached 3 ng/mL and be 25% above thenadir observed while on prior androgen ablation therapy. Patients who were treated withadjuvant or salvage radiation following radical prostatectomy, or with either luteinizinghormone-releasing hormone agonist (LHRH-a) or non-steroidal anti-androgen therapyfor a prior PSA relapse, were eligible provided PSA was not rising while receivinghormonal therapy, and 6 months had elapsed since the last effective date of androgendeprivation or anti-androgen therapy. Prior chemotherapy was permitted provided atleast 4 months had elapsed. Patients with prior orchiectomy, immunotherapy, or therapy Page 6 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  8. 8. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.with experimental agents for prostate cancer were excluded as were patients with ahistory of other prior malignancies within 5 years of study entry, other than resectedbasal or squamous cell carcinoma of the skin. Patients whose post-prostatectomy PSAreached 20 ng/mL were not eligible. Concurrent participation in other clinical trialsinvolving investigational agents was prohibited. During a run-in period, patients were treated with a 3-month depot injection of anLHRH-a. Those with PSA < 1 ng/mL following the LHRH-a were eligible forrandomization. Those with a PSA ≥ 1 ng/mL were permitted to receive an additional1-month depot injection of LHRH-a, and were eligible for randomization if PSA declinedto < 1 ng/mL. Local institutional review boards approved the protocol at each studycenter, and all patients signed institutional review board-approved informed consentforms.Randomization Assignment and Treatment This double-blind, randomized, controlled study involved 17 centers in the UnitedStates. A centrally administered, stratified, block randomization method encompassingall study centers was employed to assign patients to treatment in a 2:1 ratio(sipuleucel-T: control). Stratification variables were receipt of adjuvant or salvageradiation therapy after prostatectomy (yes or no) and Gleason score (≤ 6 or ≥ 7). Treatment was scheduled at Weeks 0, 2, and 4. An optional booster treatmentwith a single infusion of sipuleucel-T or control, as originally randomized, was availableafter BF; the blind was maintained, and there was no cross-over. Prior to eachtreatment, patients underwent a standard 1.5 to 2.0 blood volume mononuclear cellleukapheresis, which was transported to a sponsor-designated manufacturing facility. Page 7 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  9. 9. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Patients were infused 2 to 3 days after leukapheresis with sipuleucel-T or control.11Control consisted of PBMC held at 2-8°C without the addition of PA2024.Schedule of Events for Endpoint Evaluations Blood samples for PSA testing were drawn at Screening, Week -1, Week 0 (firstinfusion), Weeks 2, 13, 26, and every 3 months until distant failure. In patients receivinga booster, blood samples for PSA were collected at Weeks 4 and 13 post-booster.Distant failure was documented by observation of metastases on bone scan, CT scan,or other imaging modality. Scans were performed every 12 months following BF, orwhen triggered by one of the following events: PSA doubling within 9 months followingBF, PSA ≥ 10 ng/mL, symptomatic disease-related pain, or in accordance with clinicalpractice. Patients underwent blood draws for assessment of immune response duringregularly scheduled visits at Screening and Weeks 4 and 13 following the first infusion.Patients receiving a booster infusion underwent a blood draw for assessment ofimmune response prior to the booster infusion and at Weeks 4 and 13 post-booster.Patients were followed throughout the study for safety (physical examinations, adverseevent assessments, laboratory tests) and survival. This study is ongoing and survivalresults will be reported when available.Immunologic Testing As part of lot-release assessments, every sipuleucel-T and control product wasassessed for APC activation by the degree of CD54 upregulation, determined by theratio of CD54 expression on post-culture APCs compared to pre-culture APCs.12 Page 8 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  10. 10. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Immune responses in the peripheral blood were assessed by interferon-gamma(IFNγ) ELISPOT and proliferation assays in a subset of patients.9,13 PBMCs, freshlyisolated from whole blood, were plated in triplicate into anti-IFNγ (all antibodiespurchased from MabTECH, Sweden) coated ELISPOT plates (Millipore, MA), or roundbottom plates for proliferation assays, in the presence of PA2024 (10 µg/mL). For ELISPOT assays, plates were incubated for 48 hours, washed, probed withbiotinylated anti-IFNγ, further washed, and then incubated with streptavidin alkalinephosphatase. Spot development was achieved with BCIP/NBT (Invitrogen, CA) andspots were enumerated by a CTL Immunospot 3 reading system (CTL, OH). Thefrequency of PA2024 IFN-γ ELISPOTS was expressed as median spots abovebackground. For proliferation assays, cells were incubated for 5 days, pulsed overnight with0.5 µCi tritiated thymidine (3H) (Perkin Elmer, MA), harvested, and the amount of 3Hincorporation then determined by means of a betaplate counter (Perkin Elmer, MA). Thedegree of antigen-specific clonal T cell expansion was expressed as a stimulation index(SI) of the ratio of 3H incorporation by cells incubated with PA2024 compared to mediacontrols.Statistical Considerations Prostate specific antigen kinetics were evaluated by determining the time fromrandomization to BF, PSA velocity, and PSADT. The time to BF was the primaryefficacy endpoint of this study; the null hypothesis was that there was no difference intime to BF between the treatment arms. A sensitivity endpoint of BF was performed forconfirmed BF, defined as a second PSA value ≥ 3.0 ng/mL obtained no less than two Page 9 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  11. 11. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.but no more than four weeks after the first PSA ≥ 3.0 ng/mL. Secondary endpointsincluded PSADT, time from randomization to distant failure, and overall survival.Immunological responses using proliferation and ELISPOT assays were exploratoryendpoints. The study design was based on a sample size of 159 patients with an accrualperiod of 3 years and a 2-year follow-up period. This sample size was expected toobtain 108 events, providing 80% power to detect an increase from 1 year to 1.75 yearsin median time to BF at the 0.05 level of significance using a 2-sided log-rank test.Time to event endpoints (BF and distant failure) were tested between treatment groupsusing the 2-sided log-rank test, stratified by Gleason Score and radiation therapy.Hazard ratios and corresponding 2-sided 95% confidence intervals for each endpointwere generated under the stratified Cox regression model. Cumulative incidence wascalculated taking into consideration competing events prior to the events ofinterest.14Competing events for the primary endpoint of BF included death, loss tofollow-up, withdrawal of consent, or initiation of an excluded therapy. Median times toevents were derived from the estimated cumulative incidence curves. PSADT was estimated from PSA velocity, which was the rate change in thelogarithmic scale of PSA by time (slope). The difference between treatment groups inPSADT or PSA velocity was tested through comparison of the slope difference betweenthe groups using a mixed effect model that included factors of treatment group, time,and treatment by time interaction, with patient-specific random intercept and slope. PSAlevels below 0.2 were treated as 0.2, and PSA measurements after the initiation ofsystemic therapy were not used. Analyses were performed based on all data from Page 10 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  12. 12. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.randomization, as well as data from randomization date plus 30 days, plus 60 days, andplus 90 days, to the initiation of systemic therapy, accounting for the possibility thatimmunotherapy may require time to reach peak effect and to impact PSA kinetics.Because PSA kinetics can be influenced by testosterone recovery,15-17 and testosteronerecovery varies considerably among patients following a course of hormonaltherapy,18,19 an additional analysis was performed excluding PSA values prior totestosterone recovery (≥ 90% of the baseline value). To compare the difference in CD54 upregulation between specific visits, a linearmixed effect model was used on log-transformed upregulation ratios. To compare thedifference in immunological response between treatment groups at a specific visit, alinear mixed effect model was used on log-transformed stimulation indices based on allavailable patient visit dates. The model included treatment group, visit, treatment by visitinteraction, and patient (as a random effect). For the comparison of ELISPOT betweengroups, the same mixed effect model was used to analyze the rank-transformed data.Due to the small sample sizes and variation in timing, the Wilcoxon rank-sum test andexact p-values are reported for treatment comparisons at boost + 4 weeks and boost +13 weeks. Two-sided nominal P-values were reported for all statistical tests.RESULTSPatient Characteristics and Disposition Between July 2001 and July 2005, 208 patients entered the 3-month run-inperiod of this study. Of those patients, 176 were randomized, comprising the intent-to-treat population; 117 patients were randomized to receive sipuleucel-T and 59 patients Page 11 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  13. 13. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.were randomized to receive control. Baseline characteristics were well-balancedbetween the two treatment arms (Table 1). A total of 175 patients underwent at leastone leukapheresis procedure, comprising the safety population. Of the patients includedin the safety population, 172 received at least 1 infusion of sipuleucel-T or control.Figure 1 presents a schematic of patient disposition.Clinical Results The median time to BF was 18.0 months for sipuleucel-T and 15.4 months forcontrol (HR=0.936, [95% CI: 0.637, 1.376]; P=0.737; Figure 2A). In a sensitivity analysisexamining only BF defined by two PSA measurements equal to or above 3.0 ng/mL, theHR was 0.797 (95% CI: 0.529, 1.202; P=0.278; Figure 2B). Analyses of PSADT were performed using all PSA values from randomizationuntil the initiation of systemic therapy for prostate cancer (Figure 3). To account for thetime required for immune response to take effect and to allow for testosterone recovery,additional analyses were performed that excluded PSA values obtained at earlier timepoints in the study (Figure 3). PSADT was 34.4% greater in the sipuleucel-T armcompared with the control arm with PSA values obtained ≥ 90 days post-randomization(P=0.046). In the analysis following testosterone recovery, PSADT was 47.6% greater inthe sipuleucel-T arm compared with the control arm (P=0.038). Patients are still being followed for the secondary endpoint of time to distantfailure. As of the data cut-off date, 28 patients (15.9%, 28 of 176 patients) hadexperienced a distant failure event. With very limited power, the point estimate for risk ofdistant failure favored sipuleucel-T but lacked statistical significance (HR=0.728 [95%CI: 0.335, 1.582]; P = 0.421; Figure 2C). Page 12 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  14. 14. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Immune Parameters Antigen presenting cell activation in the sipuleucel-T arm, as measured by CD54upregulation, was greater at Week 2 and Week 4, relative to Week 0 (both P<0.001,Figure 4A), which was maintained at boost (P<0.001). In patients receiving sipuleucel-T,the median time between randomization and the booster (n=49) was 15.4 months(range 3.7 to 67.4 months). Patients on the sipuleucel-T arm demonstrated an increase in T cell proliferationto the immunizing antigen relative to patients on the control arm at Weeks 4 and 13(P<0.001; Figure 4B). The median SI for patients on the sipuleucel-T arm was 131.93and 118.50 at Weeks 4 and 13, respectively. When the immune response wasmeasured using the IFNγ ELISPOT assay, a similar treatment effect was observed atWeeks 4 and 13 (P<0.001, Figure 4C). The median number of spots for patients on thesipuleucel-T arm was 79 and 43 at Weeks 4 and 13, respectively. Immune responses were also measured prior to booster infusion in 10sipuleucel-T patients and 2 control patients, as well as post-boost in some of thesepatients (Figure 4B and 4C). T cell proliferative and ELISPOT responses in thesipuleucel-T arm were sustained at elevated levels at the pre-boost time point whencompared with control (P=0.005 and P<0.001, respectively), a median of 22.6 months(range 14.3 to 67.3 months) following randomization. After boosting, T cell proliferativeresponses appeared to be maintained, and ELISPOT responses increased in somepatients.Adverse Events Page 13 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  15. 15. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Therapy with sipuleucel-T was generally well tolerated. Similar percentages ofadverse events were observed in both treatment groups (95.7% of sipuleucel-T patientsversus 94.9% of control patients). The adverse events observed more frequently (2-fold)in the sipuleucel-T arm compared with control and in at least 10% of patients werechills, pyrexia, myalgia, influenza-like illness, and pain (Table 2). The oral parasthesiaswere temporally related to leukapheresis rather than product infusion. Of the patientsreported to have experienced an adverse event, the majority (71.4%, 125 of 175patients) had events with the greatest severity of Grade 1 or 2. Four deaths have beenreported to date; no death was considered related to treatment with sipuleucel-T. Alldeaths occurred more than one year following the last infusion of sipuleucel-T orcontrol. Adverse events observed following the booster infusion in the sipuleucel-T armand in at least 10% of the patients were fatigue, chills, pyrexia, arthralgia, and myalgia,none of which occurred in control patients receiving the booster infusion. Adverseevents occurred at a lower frequency following the booster than following the initialtreatment sequence.DISCUSSION In this study, the effect of sipuleucel-T on PSA kinetics was evaluated. The studydid not demonstrate a statistically significant difference in the primary endpoint of timeto BF. There are some important limitations of this endpoint. First, confirmation was notrequired. A sensitivity analysis that examined only confirmed BF events demonstrated ahazard ratio of 0.797 in favor of sipuleucel-T (P=0.278). Given the inherent fluctuationsin PSA,20 the requirement for a confirmatory PSA may have improved the signal-to- Page 14 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  16. 16. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.noise ratio. If this point estimate were to represent a true treatment effect, then the triallacked the statistical power to detect such a treatment effect. The primary endpoint, while reasonably selected, was also arbitrary. There areno data to suggest that reaching a PSA concentration of 3.0 ng/mL following a briefcourse of androgen suppression therapy is or is not predictive of subsequentdevelopment of metastases or cancer-related death. At the time this study wasdesigned, relatively little was known about appropriate endpoints in the setting of PSA-only relapse after radical prostatectomy. Regrettably, relatively little progress has beenmade in this area and the field continues to struggle with the design of studies in thispatient population. One area of marked progress is the increased understanding of theprognostic importance of PSA kinetics in general and PSADT specifically. PSADT hasbeen shown to be the single strongest predictor of prostate cancer related mortality inthis patient population.21-26 While fully recognizing that PSADT is not a validated endpoint for clinical trialsand to date no studies have examined the link between treatment-induced alteration inPSADT and time to disease progression or death, its prognostic importance makes it acompelling subject for exploratory analyses. These analyses showed that PSADT waslonger in patients who received sipuleucel-T, particularly after the effects of testosteronerecovery were no longer confounding the analyses. While we are not able to definitivelylink the PSADT prolongation to a treatment effect, we are encouraged by this finding.Studies that have established the prognostic importance of PSADT have largelyfocused on patients whose testosterone levels are at steady state. Because PSAkinetics are affected by early testosterone recovery,15-17 we believe an analysis after Page 15 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  17. 17. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.testosterone recovery is likely to be most informative, as previously suggested.27 Adelayed effect on PSA kinetics is also compatible with a delayed treatment effect, assuggested by the immune response to sipuleucel-T,28-30 as well as the more robusteffects of sipuleucel-T and other immunotherapies on overall survival relative to theeffects on the more proximal endpoint of disease progression.9-11,31,32 The median time to distant failure from the time of PSA elevation following radicalprostatectomy has previously been reported to be approximately 8 years.33 Since thetiming of this analysis was based on the BF endpoint, only 15.9% of patients had adistant failure event at the data cutoff date. A trend in favor of the sipuleucel-T arm wasobserved and additional follow-up for this endpoint and for overall survival may beinformative. To our knowledge, sipuleucel-T is the first autologous cellular immunotherapy todemonstrate an effect on PSA kinetics in a randomized trial. Treatment of the patientswith 3 to 4 months of an LHRH-a immediately prior to sipuleucel-T treatment may havecontributed to the observed prolongation of PSADT in the treatment arm. Recentstudies suggest a potential synergy between androgen deprivation andimmunotherapy.34 Specifically, castration or androgen deprivation therapy has beenshown to induce lymphocytosis35 and increase circulating T and NK cells in prostatecancer patients,36 induce T cell infiltration into prostate cancer tissue,37 and mitigatetolerance to therapeutic vaccination in a murine model of prostate cancer.38 Sipuleucel-T induced robust immune responses to the immunizing antigenPA2024 relative to control, as measured by both T cell proliferation and ELISPOTassays. When APC activation was measured as part of lot release assessments, there Page 16 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  18. 18. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.was significant CD54 upregulation at Week 2, Week 4, and at boost when comparedwith Week 0. The increase in APC activation from Week 0 to subsequent treatmentsprovides evidence of priming with the first dose, and boosting by subsequent infusions,indicative of the establishment of immunologic memory. The magnitude of CD54upregulation at boost, as well as the levels of T cell responses to the immunizingantigen prior to boost, indicate that sipuleucel-T generates a sustained immuneresponse, with measurements obtained as long as 67.4 months following initialtreatment. Although the sample size was small, immune responses following boosterinfusions were maintained and appear to have been augmented in some patients.Previous studies of sipuleucel-T have demonstrated evidence of correlations betweenimmune parameters and overall survival;10,11 in this study, the limited number of patientswith immune response data precluded analyses correlating the magnitude of immuneresponses with PSA kinetics. The most common treatment-related side effects observed in patientsrandomized to sipuleucel-T were fatigue, chills, and pyrexia. The majority of eventswere mild to moderate and only one patient discontinued therapy as a result of clinicaltoxicity. These results are consistent with those seen in the mCRPC population.10 In summary, this study demonstrated that treatment with sipuleucel-T was welltolerated and generated a robust and sustained immune response, consistent withprime-boosting and establishment of immunologic memory. While the primary endpointwas not met, the effect on PSADT, an important prognostic indicator in ADPC, suggeststhe biologic activity of sipuleucel-T in this population. Given evidence that sipuleucel-Tprolongs survival in men with advanced prostate cancer,9-11 long-term follow-up for Page 17 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  19. 19. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.distant failure and survival, as well as additional studies in this patient population, are ofinterest. Page 18 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  20. 20. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.REFERENCES1 Catalona WJ, Smith DS. Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer: intermediate-term results. J Urol 1998; 160:2428-34.2 Eastham JA, Scardino PT. Radical prostatectomy for clinical stage T1 and T2 prostate cancer. In: Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS, editors. Comprehensive Textbook of Genitourinary Oncology. 2 ed. Philadelphia: Lipincott, Williams, and Wilkins; 1999.3 Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 1994; 152:1831-6.4 Clark PE, Levin HS, Kupelian PA, Reddy C, Zippe CD, Klein EA. Intermediate-term outcome with radical prostatectomy for localized prostate cancer: The Cleveland Clinic experience. The Prostate Journal 2001; 3:118-25.5 Nair B, Wilt T, MacDonald R, Rutks I. Early versus deferred androgen suppression in the treatment of advanced prostatic cancer. Cochrane Database Syst Rev 2002; CD003506.6 Walsh PC, DeWeese TL, Eisenberger MA. A structured debate: immediate versus deferred androgen suppression in prostate cancer-evidence for deferred treatment. J Urol 2001; 166:508-15; discussion 15-6.7 Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005; 294:238-44.8 van Andel G, Kurth KH. The impact of androgen deprivation therapy on health related quality of life in asymptomatic men with lymph node positive prostate cancer. Eur Urol 2003; 44:209-14. Page 19 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  21. 21. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.9 Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24:3089-94.10 Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115:3670-9.11 Kantoff P, Higano C, Shore N, Berger ER, Small EJ, Penson DF, et al. A randomized, placebo-controlled, phase 3 trial of active cellular immunotherapy with Sipuleucel-T in metastatic castration-resistant prostate cancer. NEJM 2010; 363:411-22.12 Sheikh N A, Jones L A. CD54 is a marker of antigen presenting cell activation. Cancer Immunol Immunother 2008; 57(9): 1381-90.13 Park JW, Melisko ME, Esserman LJ, Jones LA, Wollan JB, Sims R. Treatment with autologous antigen-presenting cells activated with the HER-2 based antigen Lapuleucel- T: results of a phase I study in immunologic and clinical activity in HER-2 overexpressing breast cancer. J Clin Oncol 2007; 25:3680-7.14 Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine 1999; 18:695-706.15 Augustin H, Freibauer C, Bayer L, Lunglmayr G, Tschurlovich F, Kuber W, et al. Molecular markers and their prognostic impact in patients with advanced prostate cancer Page 20 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  22. 22. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. undergoing intermittent androgen suppression. Prostate Cancer Prostatic Dis 2006; 9:279-83.16 Akyol F, Ozyigit G, Selek U, Karabulut E. PSA bouncing after short term androgen deprivation and 3D-conformal radiotherapy for localized prostate adenocarcinoma and the relationship with the kinetics of testosterone. Eur Urol 2005; 48:40-5.17 Bates AT, Pickles T, Paltiel C. PSA doubling time kinetics during prostate cancer biochemical relapse after external beam radiation therapy. Int J Radiat Oncol Biol Phys 2005; 62:148-53.18 Kobayashi T, Nishizawa K, Mitsumori K. Individual variation of hormonal recovery after cessation of luteinizing hormone-releasing hormone agonist therapy in men receiving long-term medical castration therapy for prostate cancer. Scand J Urol Nephrol 2006; 40:198-203.19 Gulley JL, Aragon-Ching JB, Steinberg SM, Hussain MH, Sartor O, Higano CS, et al. Kinetics of serum androgen normalization and factors associated with testosterone reserve after limited androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2008; 180:1432-7; discussion 7.20 Riehmann M, Rhodes PR, Cook TD, Grose GS, Bruskewitz RC. Analysis of variation in prostate-specific antigen values. Urology 1993; 42:390-7.21 DAmico AV, Moul J, Carroll PR, Sun L, Lubeck D, Chen MH. Prostate specific antigen doubling time as a surrogate end point for prostate cancer specific mortality following radical prostatectomy or radiation therapy. J Urol 2004; :S42-6; discussion S6-7. Page 21 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  23. 23. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.22 Albertsen PC, Hanley JA, Penson DF, Fine J. Validation of increasing prostate specific antigen as a predictor of prostate cancer death after treatment of localized prostate cancer with surgery or radiation. J Urol 2004; 171:2221-5.23 Roberts SG, Blute ML, Bergstralh EJ, Slezak JM, Zincke H. PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Mayo Clin Proc 2001; 76:576-81.24 Sandler HM, Dunn RL, McLaughlin PW, Hayman JA, Sullivan MA, Taylor JM. Overall survival after prostate-specific-antigen-detected recurrence following conformal radiation therapy. Int J Radiat Oncol Biol Phys 2000; 48:629-33.25 Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, et al. Death in patients with recurrent prostate cancer after radical prostatectomy: prostate- specific antigen doubling time subgroups and their associated contributions to all-cause mortality. J Clin Oncol 2007; 25:1765-71.26 Valicenti RK, DeSilvio M, Hanks GE, Porter A, Brereton H, Rosenthal SA, et al. Posttreatment prostatic-specific antigen doubling time as a surrogate endpoint for prostate cancer-specific survival: an analysis of Radiation Therapy Oncology Group Protocol 92- 02. Int J Radiat Oncol Biol Phys 2006; 66:1064-71.27 Arlen PM, Bianco F, Dahut WL, D’Amico A, Figg WD, Freedland SJ, et al. Prostate Specific Antigen Working Group Guidelines on Prostate Specific Antigen Doubling Time. J Urol 2008; 179:2181-2186.28 Small EJ, Fratesi P, Reese DM, Strang G, Laus R, Peshwa MV, et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol 2000; 18:3894-903. Page 22 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  24. 24. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.29 Burch PA, Breen JK, Buckner JC, Gastineau DA, Kaur JA, Laus RL, et al. Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. Clin Cancer Res 2000; 6:2175-82.30 Burch PA, Croghan GA, Gastineau DA, Jones LA, Kaur JS, Kylstra JW, et al. Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a Phase 2 trial. Prostate 2004; 60:197-204.31 Kantoff PW, Schoetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 2010; 28(7):1099-105.32 Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010. 363(8):711-23.33 Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281:1591-7.34 Aragon-Ching JB, Williams KM, Gulley JL. Impact of androgen-deprivation therapy on the immune system: implications for combination therapy of prostate cancer. Front Biosci 2007; 12:4957-71.35 Oliver RT, Joseph JV, Gallagher CJ. Castration-induced lymphocytosis in prostate cancer: possible evidence for gonad/thymus endocrine interaction in man. Urol Int 1995; 54:226-9. Page 23 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  25. 25. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.36 Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, et al. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 2005; 175:2741-53.37 Mercader M, Bodner BK, Moser MT, Uldrich AP, Berzins SP, Heng TS, et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad Sci U S A 2001; 98:14565-70.38 Drake CG, Doody AD, Mihalyo MA, Huang CT, Kelleher E, Ravi S, et al. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. Cancer Cell 2005; 7:239-49. Page 24 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  26. 26. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Acknowledgments: We are indebted to participating patients, the additionalinvestigators (Peter Bergreen, Brendan Curti, Richard Harkaway, David Irwin, JonRichards, Deepak Sahasrabudhe, James Squadrito, Chris Teigland, Edward Weber,Jay Young) and Amy Myers, Tim Connor, Kim Miller, and Susan Moon for writingassistance, Debbi Humble and Juliet Kniley for trial conduct, Jami Wollen for immuneassays, Nancy Dawson and Frank Valone for contributions to the design and conduct ofthe trial.Grant support: The conduct of this trial was supported by Dendreon Corporation. Page 25 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  27. 27. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Table 1. Patient Characteristics Sipuleucel-T Control (n = 117) (n = 59)Age, years (median [min, max]) 64 (48,79) 67 (47,78)Race (n, %) Caucasian 105 (89.7) 54 (91.5) African American 9 (7.7) 3 (5.1) Hispanic 2 (1.7) 1 (1.7) Other 1 (0.9) 1 (1.7)ECOG performance status (n, %) 0 109 (94.8) 57 (98.3) 1 6 (5.2) 1 (1.7)Gleason Score (n, %) ≤6 34 (30.1) 15 (26.3) ≥7 79 (69.9) 42 (73.7)Prior Adjuvant Hormone Therapy (n, %) Yes 21 (17.9) 9 (15.3) No 96 (82.1) 49 (83.1)Prior Radiation Therapy (n, %) None 45 (38.5) 23 (39.0) Adjuvant 20 (17.1) 8 (13.6) Salvage 52 (44.4) 28 (47.5)Median PSA, ng/mL (min, max) Highest ever 2.3 (0.8, 33.0) 2.3 (0.8, 20.5) Prior to LHRH-a 2.1 (0.8, 16.9) 2.7 (0.8, 20.5) Prior to randomization 0.09 (0.010- 0.090 (0.010-1.00) 1.00)Abbreviations: ECOG, Eastern Cooperative Oncology Group; LHRH-a, luteinizing hormone-releasinghormone-analogue; PSA, prostate-specific antigen Page 26 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  28. 28. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Table 2.Overall Incidences of Adverse Events Occurring in ≥ 10.0 % of Patients Treated withSipuleucel-T by Frequency of Occurrence Any Gradea Grade 3-5aPreferred Term Sipuleucel-T Control Sipuleucel-T Control (n = 116) (n = 59) (n = 116) (n = 59) n (%) n (%) n (%) n (%)Any Adverse Event 111 (95.7) 56 (94.9) 31 (26.7) 18 (30.5) Fatigue 52 (44.8) 18 (30.5) 0 (0.0)) 1 (1.7) b Chills 51 (44.0) 6 (10.2) 2 (1.7) 0 (0.0) b Pyrexia 42 (36.2) 1 (1.7) 2 (1.7) 0 (0.0) Hot flush 30 (25.9) 20 (33.9) 1 (0.9) 1 (1.7) Headache 27 (23.3) 8 (13.6) 1 (0.9) 0 (0.0) Back pain 26 (22.4) 8 (13.6) 1 (0.9) 0 (0.0) Paraesthesia oral 26 (22.4) 19 (32.2) 0 (0.0) 0 (0.0) Arthralgia 25 (21.6) 8 (13.6) 1 (0.9) 0 (0.0) b Myalgia 25 (21.6) 5 (8.5) 1 (0.9) 0 (0.0) Paraesthesia 21 (18.1) 10 (16.9) 1 (0.9) 0 (0.0)) b Influenza like illness 16 (13.8) 2 (3.4) 0 (0.0) 0 (0.0) Muscle spasms 15 (12.9) 4 (6.8) 0 (0.0) 0 (0.0) b Pain 15 (12.9) 0 (0.0) 0 (0.0) 0 (0.0) Constipation 14 (12.1) 5 (8.5) 0 (0.0) 0 (0.0) Upper respiratory tract 14 (12.1) 7 (11.9) 0 (0.0) 0 (0.0) infection Diarrhoea 13 (11.2) 10 (16.9) 0 (0.0) 0 (0.0) Hypertension 13 (11.2) 8 (13.6) 0 (0.0) 0 (0.0) Nausea 13 (11.2) 4 (6.8) 0 (0.0) 0 (0.0) Dizziness 12 (10.3) 12 (20.3) 0 (0.0) 0 (0.0) Nasopharyngitis 12 (10.3) 6 (10.2) 0 (0.0) 0 (0.0)a Severity Grade assessed using National Cancer Institute’s Common Toxicity Criteria (version 2.0).b The incidence of adverse events presented in bold font was ≥2-fold larger in the sipuleucel-T arm than in the control arm. Page 27 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  29. 29. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Figure LegendsFigure 1: Patient disposition.Figure 2: Cumulative incidence of biochemical failure (sipuleucel-T, 76 events, control,41 events; each event represents a patient who reached biochemical failure, defined asa PSA value ≥ 3.0 [A]), confirmed biochemical failure (sipuleucel-T, 64 events, control38 events; each event represents a patient with confirmed biochemical failure, definedas two PSA values ≥ 3.0 taken not less than 2 but not more than 4 weeks apart [B]),and distant failure (sipuleucel-T, 17 events, control 11 events; each event represents apatient reaching distant failure, defined as radiologic evidence of metastatic lesion [C])of sipuleucel-T or control patients. Cumulative incidence was calculated consideringcompeting events (death, loss to follow-up, withdrawal of consent, and initiation ofexcluded therapy; denoted by hash marks) prior to event occurrence. Hazard ratioswere generated using stratified Cox regression model.Figure 3: PSA doubling time (PSADT) for each treatment group was estimated fromPSA velocity (rate change in the logarithmic scale of PSA by time) using a mixed effectmodel. Analyses were performed using all PSA values after randomization, PSAsobtained ≥30 days, ≥60 days, and ≥90 days after randomization, and PSAs followingtestosterone recovery (TR) to ≥90% of baseline value (prior to LHRH-a).Figure 4: CD54 upregulation (A) over time for patients treated with sipuleucel-T orcontrol. Data is fold-upregulation represented as 10th, 25th, 50th (median), 75th and 90thpercentile. Median duration from randomization to Boost was 15.4 months (range 3.7 to67.4 months) in sipuleucel-T patients. In the sipuleucel-T group, Week 2, Week 4, andBoost are significantly different compared with Week 0 (P<0.001 all), as calculated Page 28 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  30. 30. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.using a linear mixed model on log-transformed upregulation ratios. Stimulation index (B)and IFNγ ELISPOT (C) of PA2024 for patients treated with control or sipuleucel-T.Individual responses are presented in the figure. The p-value represents a comparisonof values (median shown as horizontal bars) between treatment groups at each visit. Insipuleucel-T patients with peripheral immune response data prior to Boost, the mediantime from randomization to the assessment was 22.6 months (range 14.3 to 67.3months). Page 29 of 29 Confidential Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  31. 31. Downloaded from clincancerres.aacrjournals.org on May 16, Copyright © 2011 American Association for Cancer Resea
  32. 32. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2A 2B 2C Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  33. 33. Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research
  34. 34. Author Manuscript Published OnlineFirst on May 10, 2011; DOI:10.1158/1078-0432.CCR-10-3223 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.4A 25 25 20 20 CD5 Upregulation Ratio CD54 Upregulation Ratio 15 15 10 10 54 4 5 5 0 0 Week 0 (n=113) Week 2 (n=109) Week 4 (n=109) Booster (n=49) Week 0 (n=59) Week 2 (n=59) Week 4 (n=58) Booster (n=26) P<0.001 P<0.001 P<0.0014B4C Downloaded from clincancerres.aacrjournals.org on May 16, 2011 Copyright © 2011 American Association for Cancer Research

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